Patients with open-angle glaucoma exhibit an enhanced sensitivity to topical glucocorticoids with respect to elevations of intraocular pressure. This hypersensitivity to glucocorticoids also appears to be general and is manifest when the hormone is given systemically. Thus the response of ACTH, and several responses in vitro to glucocorticoids are greater than in normals. In the present proposal, we hope to: (1) understand the molecular basis for this defect, and (2) determine which steroids may act as antiglucocorticoids in cells from glaucoma patients. To do this, we hope to examine fibroblasts cultured from patients with glaucoma and from normals. The hyperresponsiveness is preserved in the cells from the glaucoma patients. To understand the molecular basis for the hyperresponsiveness, the focus in these studies will be on the early steps in steroid action which, based on a number of considerations, are likely to contain the defect. Thus, we will determine the uptake of steroids by the cells, the quantitative interactions both agonist and antagonist steroids with the specific glucocorticoid receptors, the influence of the steroid on "activation" of the receptor-steroid complex which is necessary for nuclear binding, and the subsequent interaction of the "activated" complex with nuclear constituents. If the hyperresponsiveness of the defect can be traced to one of these elements, then the identified components will be purified and characterized. It is hoped that these studies will allow a determination of whether the hyperresponsiveness defect is associated with the early steps in steroid hormone action or are secondary to other general influences on the cell. Based on knowledge of steroid requirements for antiglucocorticoid activity in animal systems, a number of steroids will be examined for possible antagonist activity. This may suggest specific approaches to blockage of glucocorticoid responses as through topical application.